CN1665499A - 用于预防或抑制糖尿病并发症发展的药物组合物 - Google Patents
用于预防或抑制糖尿病并发症发展的药物组合物 Download PDFInfo
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- CN1665499A CN1665499A CN038152452A CN03815245A CN1665499A CN 1665499 A CN1665499 A CN 1665499A CN 038152452 A CN038152452 A CN 038152452A CN 03815245 A CN03815245 A CN 03815245A CN 1665499 A CN1665499 A CN 1665499A
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- meal
- mitiglinide
- hydrate
- diabetic
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Abstract
本发明提供药物组合物,所述药物组合物能达到血糖控制的良好状态以及校正餐后高血糖和清早禁食高血糖。本发明的药物组合物用于餐前服用以预防或抑制糖尿病并发症的发展,它包含作为单剂的5-45mg的米格列奈或其药学上可接受的盐,或者其水合物(例如,米格列奈钙盐水合物)。所述组合物对预防或抑制例如糖尿病微血管并发症和动脉硬化疾病的发展非常有用,因为药物副反应如低血糖症状和胃肠道紊乱的频率较低。
Description
技术领域
本发明涉及用于预防或抑制糖尿病并发症发展的药物组合物,所述药物组合物含有米格列奈(mitiglinide)或其药学上可接受的盐,或者其水合物,它制备为在餐前给予的药物组合物,本发明涉及该药物组合物的用法。本发明还涉及预防或抑制糖尿病并发症发展的方法,它包括在餐前给予米格列奈或其药学上可接受的盐,或者其水合物,本发明还涉及米格列奈或其药学上可接受的盐,或者其水合物在制备用于预防或抑制糖尿病并发症发展的药物组合物中的应用。
背景技术
糖尿病并发症是主要由在长时间内从慢性的、轻度的高血糖转变为严重的高血糖所引起的慢性并发症。轻度高血糖的例子包括减弱的葡萄糖耐受性(IGT)和减弱的禁食葡萄糖(IFG),这些症状会发展为糖尿病。由这些症状所伴随的并发症,可以举出例如,糖尿病微血管并发症,如糖尿病视网膜病、糖尿病肾病、糖尿病神经病等,动脉硬化疾病,如局部缺血性心脏病、脑血管疾病、闭塞性动脉硬化等。糖尿病简单地分为I型糖尿病(习惯称为先天性糖尿病或胰岛素依赖性糖尿病(IDDM)),II型糖尿病(习惯称为后天性糖尿病或非胰岛素依赖性糖尿病(NIDDM)),由于其它某种机理或紊乱所引起的糖尿病,以及妊娠性糖尿病。
当下述结果中的任一种在不同的日子所进行的两次检查中都被证实,则可以诊断病人患有糖尿病:1)偶然血浆葡萄糖不低于200mg/dL,2)清早禁食血浆葡萄糖(FPG)不低于126mg/dL,或者3)口服75g葡萄糖的耐受性试验2小时的值不低于200mg/dL。在HbA1C值不小于6.5%的情况下,即使当一次检查的结果满足任一上述标准时,也可确诊病人患有糖尿病。另一方面,减弱的葡萄糖耐受性(IGT)和减弱的禁食葡萄糖(IFG)是在这些标准下不能称为糖尿病的临界病理情况。显示清早禁食血浆葡萄糖(FGP)低于126mg/dL以及口服75g葡萄糖的耐受性试验2小时的值为140-199mg/dL的情况被认为是减弱的葡萄糖耐受性(IGT),显示清早禁食血浆葡萄糖(FGP)为110-125mg/dL以及口服75g葡萄糖的耐受性试验2小时的值低于140mg/dL的情况被认为是减弱的禁食葡萄糖(IFG)(参见参考文献1)。
血糖控制被确立为治疗这些糖尿病人的一个目标,目的是通过保持他们的血糖控制的良好状态来保持他们的日常生活质量(QOL)与健康人类似,并确保他们像健康人一样地生活,此外,也为了预防糖尿病微血管并发症(糖尿病视网膜病、糖尿病肾病、糖尿病神经病等)和动脉硬化疾病(局部缺血性心脏病、脑血管疾病、闭塞性动脉硬化等)的发生和发展。因此,也推荐具有减弱的葡萄糖耐受性或减弱的禁食葡萄糖的病人改善生活方式。HbA1C值是用于上述血糖控制的主要指征,其目标值较佳是不超过7%,更好是小于6.5%。另外,餐后2小时血浆葡萄糖的值和禁食血浆葡萄糖值也用作HbA1C值的辅助指征。餐后2小时血浆葡萄糖的值和禁食血浆葡萄糖的目标值分别为200mg/dL和100-140mg/mL(参见参考文献2-3)。
最近,在英国对II型糖尿病的大规模临床研究中,确认了血糖控制对治疗或抑制糖尿病和糖尿病并发症发展的重要性。例如,HbA1C值减小0.9%就可导致与糖尿病相关的死亡率下降10%,并且还报道了心肌梗塞和微血管并发症的发生分别显著地减少了16%和25%,血糖控制提供了对糖尿病并发症的发生和发展的良好影响(参见参考文献4)。此外,还报道了HbA1C值超过7.5%会导致显性糖尿病肾病发生的频率增加,而在禁食血浆葡萄糖为140mg/dL或140mg/dL以上的情况下,糖尿病视网膜病发生频率增加。
如上所述,血糖控制对预防或抑制糖尿病和糖尿病并发症的发展非常重要,为了保持血糖控制的良好状态,需要根据所用药物的种类、活性、处理(disposition)等,依据仔细的给药计划,以合适的用法给予适宜的剂量。另外,要注意的是血糖控制不能引起任何长时间的低血糖,并且要稳定地控制当天血液葡萄糖水平,包括餐后和禁食血液葡萄糖。
米格列奈钙盐水合物(化学名称:(+)-双[(2S,3a,7a-顺式)-α-苄基六氢-γ-氧代-2-异吲哚啉丁酸单钙]二水合物)是具有以下化学结构的快速及短时间作用的胰岛素促分泌素,并且已知为期望用作校正餐后高血糖状态的化合物。但是,没有任何有关米格列奈的处理,其用于血糖控制的使用方法等的报道。
另外,还报道了包含作为活性成分的米格列奈钙盐水合物的速释制剂。但是,它仅仅是一种速释制剂,没有描述米格列奈的处理,也没有描述其用于血糖控制。
参考文献1:“糖尿病治疗指南2002-2003”,日本糖尿病协会编辑,第1版,Bunkodo公司,2002年5月9日,第14-15页;
参考文献2:“糖尿病治疗指南2002-2003”,日本糖尿病协会编辑,第1版,Bunkodo公司,2002年5月9日,第18-19页;
参考文献3:“今日的治疗药物,解说和便览”,Yu Mizushima编辑,第24版,南廣堂,2002年3月15日,第297页;
参考文献4:“柳叶刀”,1998年9月12日,第352卷,No.9131,第837-853页;
参考文献5:日本专利公报No.356459/1992;
参考文献6:国际专利公报No.2000/71117。
发明内容
本发明的发明人对米格列奈或其药学上可接受的盐,或者其水合物的活性和处理进行了认真的研究,创立了合适的剂量和用法。使用基于这些研究得到的发现来制备的药物组合物,发明人进行了下述临床研究。结果,发现通过以下述方式给予米格列奈钙盐水合物,可以达到极好的血糖控制,并有效地抑制餐后高血糖,此外,还能抑制清早禁食高血糖,并且相关的低血糖症状和胃肠道紊乱的发生频率较低,所述剂量和用法能非常有效地预防或抑制糖尿病并发症的发展,由此完成了本发明。
本发明提供了一种用于预防或抑制糖尿病并发症发展的极好的药物组合物及其用法。
更具体地说,本发明者发现,显著减小HbA1C值所需的米格列奈或其药学上可接受的盐,或者其水合物所需的剂量为单剂5mg及5mg以上,并且所述药剂的处理半衰期约为1.5小时。基于上述发现,本发明者估计了适宜的剂量和用法,结果发现,通过在每餐前(在开始用餐前的10分钟内),较好是恰在餐前(在开始用餐前的5分钟内)给予5-45mg,或者较好是5-22mg米格列奈钙盐水合物,一日三次,服用4周或4周以上,可以显著地减小HbA1C值并改善血糖控制,另外,低血糖症状和胃肠道紊乱如腹部肠气发生的频率较低。而且,还发现餐后血液葡萄糖水平的增加被明显抑制,即使在餐后2小时也能发挥极好的低血糖作用,另外,早餐禁食血浆葡萄糖也被明显抑制。本发明基于这些发现来完成。
即,本发明涉及一种用于预防或抑制糖尿病并发症发展的药物组合物,所述药物组合物为用于餐前给药而制备,包含作为单剂的5-45mg的米格列奈或其药学上可接受的盐,或者其水合物。
本发明还涉及一种用于血糖控制的方法和一种预防或抑制糖尿病并发症发展的方法,它包括在餐前给予作为单剂的5-45mg的米格列奈或其药学上可接受的盐,或者其水合物。
而且,本发明还涉及米格列奈或其药学上可接受的盐,或者其水合物在制备用于预防或抑制糖尿病并发症发展的上述药物组合物中的应用。
以下,将进一步详细地描述本发明。
在本发明中,术语“餐后高血糖”是指餐后血浆葡萄糖(PPG)的1小时值和/或2小时值不低于200mg/dL,包括偶然血浆葡萄糖水平或口服75g葡萄糖耐受性试验的2小时水平不低于200mg/dL。另外,术语“禁食高血糖”是指清早禁食血浆葡萄糖(FPG)不低于126mg/dL。
本发明的目标患者是具有糖尿病并发症的II型糖尿病人,具有患糖尿病并发症危险的具有减弱的葡萄糖耐受性(IGT)和减弱的禁食葡萄糖(IFG)的病人,或者II型糖尿病人。作为一个优选的例子,举出了具有餐后高血糖的病人,还举出了伴有禁食高血糖的患有餐后高血糖的病人。作为糖尿病并发症,举出了例如,糖尿病微血管并发症,如糖尿病视网膜病、糖尿病肾病、糖尿病神经病等,动脉硬化疾病,如局部缺血性心脏病(心肌梗塞、心绞痛等)、脑血管疾病(脑梗塞等)、闭塞性动脉硬化等。作为米格列奈的药学上可接受的盐,可以举出与无机碱形成的盐,如钠盐、钾盐、钙盐等,与有机胺形成的盐或氨基酸的盐,如吗啉、哌啶、苯丙氨酸等,优选钙盐。另外,作为本发明的活性成分,最优选米格列奈钙盐水合物。为了保持血糖控制的良好状态,优选口服作为单剂的5-45mg的米格列奈或其药学上可接受的盐,或者其水合物,按上述方式服用,可以改善血糖控制以及餐后血浆葡萄糖的1小时和2小时值和清早禁食血浆葡萄糖水平。作为单剂的量,优选5-22mg,更好是使用10-11mg米格列奈钙盐水合物。给药方法是基本上在餐前(在开始用餐前的10分钟内)给予,或者较好是恰在餐前(在开始用餐前的5分钟内)给予,一日三次,治疗周期较好是4周或4周以上。另外,最优选的是在餐前(在开始用餐前的10分钟内),较好是恰在餐前(在开始用餐前的5分钟内)给予作为单剂的10-11mg的米格列奈钙盐水合物(根据症状来调节剂量),一日三次,持续4周或4周以上。
作为本发明的活性成分的米格列奈或其药学上可接受的盐,或者其水合物可以通过日本专利公报No.356459/1992、日本专利公报No.340622/1994和日本专利公报No.340623/1994中描述的方法或类似的方法容易地制备。
作为本发明中使用的药物组合物,可以举出口服药物组合物,如颗粒剂、细颗粒剂、粉末剂、片剂、胶囊等。
这些药物组合物可通过以药学上通常使用的方法与适宜的药物添加剂,如稀释剂、粘合剂、表面活性剂、润滑剂、助流剂、包衣材料、增塑剂、着色剂、调味剂等进行混合,并根据常规方法配制来制备。
稀释剂可包括,例如纤维素或纤维素衍生物,如微晶纤维素等;淀粉或淀粉衍生物,如玉米淀粉、小麦淀粉、环糊精等;糖或糖醇,如乳糖、D-甘露糖醇等;以及无机稀释剂,如干的氢氧化铝凝胶、沉淀的碳酸钙、铝硅酸镁、磷酸氢钙等。
粘合剂可包括,例如羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、糊精、支链淀粉、羟丙基淀粉、聚乙烯醇、***胶、琼脂、明胶、西黄蓍胶、聚乙二醇等。
表面活性剂可包括,例如脂肪酸的蔗糖酯、硬脂酸聚烃氧基酯、聚氧乙烯氢化的蓖麻油、聚氧乙烯聚丙二醇、失水山梨糖醇倍半油酸酯、失水山梨糖醇三油酸酯、失水山梨糖醇单硬脂酸酯、失水山梨糖醇单棕榈酸酯、失水山梨糖醇单月桂酸酯、聚山梨糖醇、单硬脂酸甘油酯、十二烷基硫酸钠、月桂基聚乙二醇等。
润滑剂可包括,例如硬脂酸、硬脂酸钙、硬脂酸镁、滑石等。
助流剂可包括,例如无水氢氧化铝凝胶、硅酸镁等。
包衣材料可包括,例如羟丙基甲基纤维素2910、氨基烷基甲基丙烯酸酯共聚物E、聚乙烯醇缩乙醛二乙氨基乙酸酯、聚乙二醇6000、氧化钛等。
增塑剂可包括,例如柠檬酸三乙酯、三醋精、聚乙二醇6000等。
在本发明的药物组合物中,优选速释制剂,它可通过,例如国际专利公报No.2000/71117中描述的方法或类似的方法来配制。
在本发明的药物组合物中,用于糖尿病并发症的其它药物可适宜地与作为活性成分的米格列奈或其药学上可接受的盐,或者其水合物组合(混合)。此外,本发明的药物组合物可适宜地与用于糖尿病并发症的其它药物同时或不同时(组合)使用。用于糖尿病并发症的药物的例子包括醛糖还原酶抑制剂(缓泻药等)、钠通道拮抗剂(盐酸美西律等)、血管紧张素转换酶抑制剂(盐酸咪达普利、赖诺普利等)、血管紧张素II受体拮抗剂(洛沙坦钾、伊贝沙坦等)等。此外,类似地,也可以适宜地结合或混合其它低血糖药物。可用来与本发明的化合物结合的低血糖药物包括胰岛素敏感性增强剂(盐酸吡咯列酮、马来酸罗格列酮等)、葡萄糖吸收抑制剂(伏格列波糖、阿卡波糖、米格列醇等)、双胍(盐酸甲福明、盐酸丁福明等)、胰岛素分泌增强剂(甲苯磺丁脲、醋磺环己脲、妥拉磺脲、氯磺丙脲、优降糖、格列本脲/优降糖、格列齐特、谷胱甘肽等)、以及胰岛素制备剂等。
具体实施方式
实施例
通过以下试验例和实施例进一步详细地描述本发明。但是,本发明不限于它们。
实施例1
在用50.0g米格列奈钙盐水合物混合275.0g微晶纤维素、279.0g乳糖、100.0g玉米淀粉、30.0g低取代的羟丙基纤维素(商品名:L-HPC/LH-11,由Shin-EtsuChemical有限公司生产)、8.0g硬脂酸钙和8.0g轻质无水硅酸(商品名:AdsolideTM101,由Freund Industrial有限公司生产)之后,用压片机挤压该混合物以制备具有下述组成的片剂:
活性成分 10.0mg
微晶纤维素 55.0mg
乳糖 55.8mg
玉米淀粉 20.0mg
低取代的羟丙基纤维素 6.0mg
硬脂酸钙 1.6mg
轻质无水硅酸 1.6mg
[总计] 150.0mg
实施例2
在用55.0g米格列奈钙盐水合物混合275.0g微晶纤维素、274.0g乳糖、100.0g玉米淀粉、30.0g低取代的羟丙基纤维素(商品名:L-HPC/LH-11,由Shin-EtsuChemical有限公司生产)、8.0g硬脂酸钙和8.0g轻质无水硅酸(商品名:AdsolideTM101,由Freund Industrial有限公司生产)之后,用压片机挤压该混合物以制备具有下述组成的片剂:
活性成分 11.0mg
微晶纤维素 55.0mg
乳糖 54.8mg
玉米淀粉 20.0mg
低取代的羟丙基纤维素 6.0mg
硬脂酸钙 1.6mg
轻质无水硅酸 1.6mg
[总计] 150.0mg
试验例1
溶出试验
对于以下片剂,使用900mL日本药典的第一液体作为试验溶液,根据第13次修订的日本药典的搅拌法,在溶出试验方法所用的设备2中以50rpm的速度进行溶出试验。
[表1]
表 | 在试验开始后20分钟时的溶出% |
实施例1 | >75 |
实施例2 | >75 |
在试验开始后20分钟时的溶出%的结果示于表1。已经确认实施例1-2的这些片剂在日本药典的第一液体中释放75%所需的溶解时间不超过20分钟。
实施例3
对II型糖尿病人的临床研究
使用实施例1描述的药物组合物,在下述条件下对II型糖尿病人进行临床研究。
对象标准:食疗不能够达到足够的血糖控制的II型糖尿病人,更具体地说,该对象在开始服用试验药物之前已经接受了8周以上的食疗,但是两次HbA1C测定值不小于6.5%,并且餐后血浆葡萄糖(PPG)的1小时或2小时值不小于200mg/dL。
试验药物和给药方式:每位病人恰在餐前(在开始用餐前的5分钟内)口服选自以下组合组中的任一种或它们的组合(每人一片),一日三次:
本发明组:(1)+(4)
正对照组:(2)+(3)
正对照组:(3)+(4)
(1)包含10mg米格列奈钙盐水合物的片剂;
(2)包含0.2mg伏格列波糖(化学名:(+)-1L-[1(OH),2,4,5/3]-5-[2-羟基-1-(羟甲基)-乙基]氨基-1-顺式-(羟甲基)-1,2,3,4-环己烷三醇)的片剂;
(3)不含任何活性成分(米格列奈钙盐水合物)的安慰剂片剂;
(4)不含任何活性成分(伏格列波糖)的安慰剂片剂。
治疗周期:12周。
观察项目:在给药之前、在给药开始后某一固定的时间、以及在给药完成后后测定以下项目,并且计算它们的变化,或者计算药物副反应的发生频率,然后评价。
[1]HbA1C值的变化
[表2]
治疗组 | 平均值(%) | |||
4周 | 8周 | 12周 | 最终评价 | |
本发明组 | -0.30 | -0.46 | -0.46 | -0.44 |
正对照组 | -0.14 | -0.14 | -0.11 | -0.11 |
安慰剂组 | 0.02 | 0.14 | 0.22 | 0.21 |
有关HbA1C值的变化的结果示于上表2中。与作为正对照的伏格列波糖和安慰剂相比,在开始给药的4周后米格列奈钙盐水合物显著地减小了HbA1C值,并且与安慰剂相比,伏格列波糖显著地减小了HbA1C值。从上述结果可以确认,米格列奈钙盐水合物显示出减小HbA1C值的有效活性,并且具有改善血糖控制状态的极好的功效。
[2]清早禁食血浆葡萄糖(FPG)的变化
[表3]
治疗组 | 平均值(mg/dL) |
本发明组 | -8.0 |
正对照组 | 0.5 |
安慰剂组 | 7.1 |
有关清早禁食血浆葡萄糖(FPG)的变化的结果示于上表3(表中的平均值表示最后评价时的值)中。与作为正对照的伏格列波糖和安慰剂相比,米格列奈钙盐水合物显著地降低了清早禁食血浆葡萄糖(FPG)。因此,已经确认,米格列奈钙盐水合物显示出降低清早禁食血浆葡萄糖(FPG)的有效活性。
[3]餐后血浆葡萄糖(PPG)的1小时和2小时值的变化
[表4]
治疗组 | 平均值(mg/dL) | |
PPG的1小时值 | PPG的2小时值 | |
本发明组 | -53.1 | -50.1 |
正对照组 | -24.8 | -5.1 |
安慰剂组 | 7.1 | 9.9 |
有关餐后血浆葡萄糖(PPG)的1小时和2小时值的变化的结果示于上表4(表中的平均值表示最后评价时的值)中。与作为正对照的伏格列波糖和安慰剂相比,米格列奈钙盐水合物显著地减小了餐后血浆葡萄糖(PPG)的1小时和2小时值。因此,已经确认,米格列奈钙盐水合物显示出减小餐后血浆葡萄糖(PPG)的有效活性。
[4]低血糖症状和胃肠道紊乱的药物副反应的发生频率
[表5]
治疗组 | 频率(%) | |
低血糖症状 | 胃肠道紊乱 | |
本发明组 | 2.0 | 17.6 |
正对照组 | 4.5 | 24.5 |
安慰剂组 | 2.9 | 16.7 |
有关低血糖症状和胃肠道紊乱的药物副反应的发生频率的结果示于上表5中。与作为正对照的伏格列波糖相比,米格列奈钙盐水合物减少了低血糖症状和胃肠道紊乱如腹部肠气增加的发生频率。因此,已经确认,米格列奈钙盐水合物是具这些药物副反应的发生率较低的安全性高的试剂。
实施例4
对给药时间选择的临床研究
用健康的成年男性来评价进餐前的给药时间选择。使用的试验药物是包含10mg米格列奈钙盐水合物的片剂和安慰剂片剂。在开始进餐前的0.5分钟、5分钟、10分钟或30分钟服用包含10mg米格列奈钙盐水合物的片剂(正组),而安慰剂片剂在开始进餐前的0.5分钟服用。服用后,在开始进餐时测定血液葡萄糖水平,并进行评价。
[表6]
治疗组 | 给药时间选择 | 平均值(mg/dL) |
正组 | 在开始进餐前的0.5分钟 | 87.0 |
在开始进餐前的5分钟 | 83.8 | |
在开始进餐前的10分钟 | 84.2 | |
在开始进餐前的30分钟 | 55.7 | |
安慰剂组 | 在开始进餐前的0.5分钟 | 85.6 |
结果示于上表6中。当在开始进餐前的10分钟内服用时,米格列奈钙盐水合物能够保持良好的血液葡萄糖水平,而在开始进餐前30分钟服用时,血液葡萄糖水平显著地降低。因此,已经确认,通过在开始进餐前的10分钟内服用米格列奈钙盐水合物,能够降低发生低血糖的风险。另外,从给药顺应性的角度考虑,优选地在开始进餐前的5分钟内服用。
工业应用性
本发明能提供临床上有效的、极好的用于预防或抑制糖尿病并发症发展的药物组合物,所述药物组合物能达到血糖控制的良好状态和校正餐后高血糖和清早禁食高血糖,此外,它还具有较低的不利药物反应如低血糖症状和胃肠道紊乱的发生频率。
Claims (16)
1.一种用于预防或抑制糖尿病并发症发展的药物组合物,所述药物组合物为用于餐前服用而制备,包含米格列奈或其药学上可接受的盐,或者其水合物,其特征在于,单剂给药量为5-45mg。
2.如权利要求1所述的药物组合物,其特征在于,所述组合物为用于恰在餐前服用而制备。
3.如权利要求1或2所述的药物组合物,其特征在于,所述组合物一天服用三次,在各餐之前服用,服用4周或4周以上。
4.如权利要求1-3中任一项所述的药物组合物,其特征在于,所述单剂给药量为5-22mg。
5.如权利要求4所述的药物组合物,其特征在于,所述单剂给药量为10-11mg,活性成分为米格列奈钙盐水合物。
6.如权利要求1-5中任一项所述的药物组合物,其特征在于,在日本药典的第一液体中释放75%所需的溶解时间为20分钟或20分钟以下。
7.如权利要求1-6中任一项所述的药物组合物,其特征在于,所述糖尿病并发症是糖尿病微血管并发症。
8.如权利要求7所述的药物组合物,其特征在于,所述糖尿病微血管并发症是糖尿病视网膜病。
9.如权利要求7所述的药物组合物,其特征在于,所述糖尿病微血管并发症是糖尿病肾病。
10.如权利要求1-6中任一项所述的药物组合物,其特征在于,所述糖尿病并发症是动脉硬化疾病。
11.一种预防或抑制糖尿病并发症发展的方法,它包括在餐前服用作为单剂的5-45mg的米格列奈或其药学上可接受的盐,或者其水合物。
12.如权利要求11所述的方法,其特征在于,所述单剂是5-22mg。
13.如权利要求12所述的方法,其特征在于,所述单剂是10-11mg,活性成分为米格列奈钙盐水合物。
14.如权利要求11-13中任一项所述的方法,其特征在于,一天服用三次。
15.如权利要求11-14中任一项所述的方法,其特征在于,治疗周期是4周或4周以上。
16.米格列奈或其药学上可接受的盐,或者其水合物在制备权利要求1-10中任一项所述的药物组合物中的应用。
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JP2002189559 | 2002-06-28 | ||
JP189559/2002 | 2002-06-28 |
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CN1665499A true CN1665499A (zh) | 2005-09-07 |
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CN038152452A Pending CN1665499A (zh) | 2002-06-28 | 2003-06-26 | 用于预防或抑制糖尿病并发症发展的药物组合物 |
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US (2) | US20050215607A1 (zh) |
EP (1) | EP1552830A4 (zh) |
JP (1) | JPWO2004002474A1 (zh) |
KR (1) | KR100709531B1 (zh) |
CN (1) | CN1665499A (zh) |
AU (1) | AU2003244083A1 (zh) |
CA (1) | CA2489660A1 (zh) |
TW (1) | TW200403054A (zh) |
WO (1) | WO2004002474A1 (zh) |
Cited By (1)
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CN103565764A (zh) * | 2013-11-26 | 2014-02-12 | 重庆科瑞南海制药有限责任公司 | 米格列奈钙组合物片剂及其制备方法 |
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WO2005107746A1 (ja) * | 2004-05-11 | 2005-11-17 | Kissei Pharmaceutical Co., Ltd. | 脂質代謝異常の予防または治療用医薬組成物 |
JP4955392B2 (ja) * | 2004-07-01 | 2012-06-20 | キッセイ薬品工業株式会社 | 血管内膜過増殖疾患の予防または治療剤 |
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US5428066A (en) * | 1989-03-08 | 1995-06-27 | Larner; Joseph | Method of reducing elevated blood sugar in humans |
JP2686863B2 (ja) * | 1991-04-25 | 1997-12-08 | キッセイ薬品工業株式会社 | 新規なベンジルコハク酸誘導体 |
FR2765578B1 (fr) * | 1997-07-03 | 1999-09-10 | Adir | Procede de preparation d'un perhydroisoindole substitue |
JP4063386B2 (ja) * | 1998-01-29 | 2008-03-19 | キッセイ薬品工業株式会社 | 速放性経口医薬品組成物 |
AU782005B2 (en) * | 1999-05-21 | 2005-06-30 | Kissei Pharmaceutical Co. Ltd. | Immediate release medicinal compositions for oral use |
EP1295609A4 (en) * | 2000-02-24 | 2004-11-03 | Takeda Chemical Industries Ltd | DRUGS CONTAINING COMBINED ACTIVE INGREDIENTS |
JP4917712B2 (ja) * | 2000-02-24 | 2012-04-18 | 武田薬品工業株式会社 | 併用医薬 |
RU2281764C2 (ru) * | 2000-03-17 | 2006-08-20 | Адзиномото Ко., Инк. | Лекарственные средства для лечения осложнений, связанных с диабетом, и невропатии и их применения |
FR2834892B1 (fr) * | 2002-01-23 | 2004-02-27 | Servier Lab | Composition pharmaceutique orodispersible de mitiglinide |
US6830759B2 (en) * | 2002-06-28 | 2004-12-14 | Ajinomoto Co., Inc. | Antidiabetic preparation for oral administration |
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2003
- 2003-06-26 KR KR1020047021405A patent/KR100709531B1/ko active IP Right Grant
- 2003-06-26 JP JP2004517287A patent/JPWO2004002474A1/ja active Pending
- 2003-06-26 US US10/519,155 patent/US20050215607A1/en not_active Abandoned
- 2003-06-26 CA CA002489660A patent/CA2489660A1/en not_active Abandoned
- 2003-06-26 AU AU2003244083A patent/AU2003244083A1/en not_active Abandoned
- 2003-06-26 EP EP03761816A patent/EP1552830A4/en not_active Withdrawn
- 2003-06-26 CN CN038152452A patent/CN1665499A/zh active Pending
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- 2003-06-27 TW TW092117572A patent/TW200403054A/zh unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103565764A (zh) * | 2013-11-26 | 2014-02-12 | 重庆科瑞南海制药有限责任公司 | 米格列奈钙组合物片剂及其制备方法 |
CN103565764B (zh) * | 2013-11-26 | 2016-08-31 | 重庆科瑞南海制药有限责任公司 | 米格列奈钙组合物片剂及其制备方法 |
Also Published As
Publication number | Publication date |
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JPWO2004002474A1 (ja) | 2005-10-27 |
KR100709531B1 (ko) | 2007-04-23 |
US20050215607A1 (en) | 2005-09-29 |
KR20050016936A (ko) | 2005-02-21 |
AU2003244083A1 (en) | 2004-01-19 |
EP1552830A4 (en) | 2007-07-18 |
WO2004002474A1 (ja) | 2004-01-08 |
TW200403054A (en) | 2004-03-01 |
CA2489660A1 (en) | 2004-01-08 |
US20090018181A1 (en) | 2009-01-15 |
EP1552830A1 (en) | 2005-07-13 |
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